HIV infection depends upon the coordinated binding of gp120 to human CD4 receptors followed by significant conformational reorganization of gp120, which results in binding to CCR5 or CXCR4 receptor. Directly interfering with viral life cycle by targeting gp120 is a promising therapeutic approach, given the recent success of a multivalent CD4-lgG2 based gp120 inhibitor, which has progressed to phase II clinical trials. Moreover recently published crystal structures of gp120 complexed with CD4 suggest how a beta- sheet based inhibitor scaffold can be utilized for abrogating gp120/CD4 interactions and thereby viral entry. We have recently developed a novel method for presenting stable beta-sheets for recognition of protein surfaces. Our thermostable beta-sheet scaffolds can bind human Immunoglobulins through a helical face, while binding a target protein (gp120) with its beta-sheet face. Based on these observations and our experience, our long-term goals are to provide new methodologies for targeting viral entry by creating CD4 mimetics based upon our miniature protein scaffolds. Our specific objectives are: A) Utilize computer guided docking to graft gp120-binding residues from CD4 upon our beta-sheet scaffold and optimize the interactions by directed evolution. B) Construct multivalent analogues of our beta-sheet inhibitors that can engage gp120 trimers and possibly spikes with very high-affinity that may surpass binding constants of known inhibitors of the gp120/CD4 interaction. C) Finally, we will test the hypothesis that our CD4 mimetics and their multivalent analogs can recruit endogenous bystander antibodies, which will prevent CCR5 and CXCR4 mediated viral entry by a unique steric blockage mechanism. A battery of cellular, biochemical, and biophysical assays will verify the success of our three interconnected approaches towards viral entry inhibitors and in the long-term provide new mini-protein therapeutics for antiviral therapy.